Transactive response DNA-binding protein 43 is enriched at the centrosome in human cells

Area of Science:

• Cell Biology
• Neuroscience
• Molecular Biology

Background:

• The centrosome is a critical organelle for microtubule organization, cell polarity, genome stability, and ciliogenesis.
• Recent findings indicate the presence of ribosomes, RNA-binding proteins, and transcripts within centrosomes, suggesting localized protein synthesis.
• TDP-43, a conserved RNA-binding protein, is implicated in the pathology of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD).

Purpose of the Study:

• To investigate the potential enrichment of TDP-43 at the centrosome.
• To explore the functional implications of TDP-43 localization at the centrosome in cellular processes and disease pathogenesis.

Main Methods:

• Sub-diffraction microscopy was employed to visualize TDP-43 localization at the centrosome in human cells across all cell cycle phases.
• Western blot and immunofluorescence microscopy were used to confirm TDP-43 presence on purified centrosomes.
• Co-localization studies with pericentrin identified TDP-43's pericentriolar enrichment.
• Analysis of TDP-43 interactors identified centrosomal mRNAs and proteins.

Main Results:

• A novel localization of TDP-43 was discovered at the centrosome throughout the cell cycle in human cells.
• TDP-43 was confirmed to be enriched in the pericentriolar region of the centrosome.
• Four conserved centrosomal mRNAs and 16 centrosomal proteins were identified as direct TDP-43 interactors.
• All 16 identified TDP-43-interacting proteins are implicated in the pathophysiology of TDP-43 proteinopathies.

Conclusions:

• TDP-43 is newly identified at the centrosome, suggesting a role for this organelle in TDP-43 physiology and pathology.
• The centrosomal enrichment of TDP-43 and its interaction with specific mRNAs and proteins, particularly those linked to neurodegeneration, highlight a potential mechanism for TDP-43-related diseases.
• This discovery opens new avenues for understanding TDP-43 function and its contribution to neurodegenerative disorders like ALS and FTLD.